IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Rudragouda Channappanavar, Anthony R. Fehr, Jian Zheng, Christine Wohlford-Lenane, Juan E. Abrahante, Matthias Mack, Ramakrishna Sompallae, Paul B. McCray, David K. Meyerholz, Stanley Perlman

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication; increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs; and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

Original languageEnglish (US)
Pages (from-to)3625-3639
Number of pages15
JournalJournal of Clinical Investigation
Volume129
Issue number9
DOIs
StatePublished - Sep 3 2019

Bibliographical note

Funding Information:
We thank Josalyn Cho for careful review of this manuscript. We thank Michael Gale Jr. (University of Washington), Westley Reeves, and Shizuo Akira for providing the MAVS-/- and TLR7-/- mice. This work was supported in part by grants from the NIH (PO1AI060699 and RO1AI129269, to SP and R21AG060222, to RC).

Funding Information:
We thank Josalyn Cho for careful review of this manuscript. We thank Michael Gale Jr. (University of Washington), West- ley Reeves, and Shizuo Akira for providing the MAVS–/– and TLR7–/– mice. This work was supported in part by grants from the NIH (PO1AI060699 and RO1AI129269, to SP and R21AG060222, to RC).

Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.

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